The present invention relates to therapeutic combinations of (S)-2-(benzylaminomethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxin[2,3-e]indol-8-one, a partial agonist of the dopamine D2/D3 receptors, and antipsychotic agents, for the treatment or prophylaxis of psychotic disorders, to pharmaceutical compositions containing said combinations, and to their use in the treatment or prophylaxis of psychotic disorders.
Psychoses are serious mental illnesses characterized by defective or lost contact with reality. These disorders are characterized by a variety of symptoms which are classified as positive symptoms (disordered thought, hallucinations, and delusions), negative symptoms (social withdrawal and unresponsiveness), and cognitive deficits.
Neuroleptics or antipsychotics can be used to treat schizophrenia and other related psychotic disorders by blocking the dopaminergic neurotransmission in the central nervous system. Neuroleptics are used widely to treat the xe2x80x9cpositivexe2x80x9d symptoms of schizophrenia. However, many of these drugs are not considered to be effective for the treatment of xe2x80x9cnegativexe2x80x9d symptoms of schizophrenia and may in fact exacerbate these symptoms because of the dopaminergic blockade associated with their mechanism of action. Cognitive deficits associated with schizophrenia, such as distractability, and executive skills such as a working memory and ability to plan, are also believed to be negatively effected by the blockade of dopamine receptors.
In addition, these neuroleptics have important side effects such as akathisia, dystonia, Parkinsonism dyskinesia and late dyskinesia and the like, which are caused by blocking the dopaminergic neurotransmission.
Anticholinergic agents such as Cogentin(copyright), have been used to reduce Parkinson-like side effects, but also cause side effects such as mental and/or physical impairment, tachycardia, dysuria and gastrointestinal symptoms.
Some partial dopamine agonists with relatively high intrinsic activity have been shown to have effectiveness against the negative symptoms of schizophrenia. It has been hypothesized that in this respect, some intrinsic activity is desirable to optimize the treatment of negative symptoms while minimizing side effects. Lindenmayer, J. P., Acta Psychiatrica Scand. 1995:91 (supp. 388):15-19.
However, with increasing intrinsic activity, levels of dopamine transmission are higher and thus, positive symptoms may be less effectively treated.
It has been found that partial dopamine agonists having moderate to high intrinsic activity, such as preclamol, pramipexole and terguride have been useful in reversing the side effects of traditional neuroleptics. These reports indicate that higher intrinsic activity leads to greater effectiveness in alleviating motor dysfunction-related side effects. Svensson, et al., Neuropharmacology, 32(10):1037-1045 (1993).
New combination drug therapies may be useful for treatment of patients. It is greatly desired to optimize the beneficial properties of both drugs, while minimizing the side effects associated with the drugs when given alone. Applicants have found useful therapeutic combination for the treatment of psychotic disorders.